The Importance of Photosensitivity for Epilepsy 3319050796, 9783319050799

Citation preview

The Importance of Photosensitivity for Epilepsy Dorothee Kasteleijn-Nolst Trenite Editor

123

The Importance of Photosensitivity for Epilepsy

Dorothee Kasteleijn-Nolst Trenite Editor

The Importance of Photosensitivity for Epilepsy

Editor Dorothee Kasteleijn-Nolst Trenite Department of Neurosurgery and Epilepsy University Medical Center Utrecht Utrecht The Netherlands Nesmos Department, Faculty of Medicine and Psychology Sapienza University Rome Italy

ISBN 978-3-319-05079-9    ISBN 978-3-319-05080-5 (eBook) https://doi.org/10.1007/978-3-319-05080-5 © Springer Nature Switzerland AG 2021 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my dear Mother who all along encouraged me to learn, work and pursue my scientific ambitions, despite being married with children as she was. Without her support till her very end in 2020, this book on photosensitivity would not likely have emerged.

Foreword

I have read with great interest this excellent multiauthored comprehensive book edited by Dorothee Kasteleijn-Nolst Trenite which addresses all aspects of photosensitivity. The book is very well planned and structured and eminently readable. It consists of 34 chapters which are grouped into five themed parts. Each chapter gives the background and history of the relevant subject as well as the most recent developments and advances in the field and a discussion of possible future research. The titles of the themes and of the chapters frequently end with a question mark, suggesting that, despite the voluminous literature on this subject, there still remains a lot to be discovered. For example, although photosensitivity appears to be a genetic trait and was thought to be autosomal dominant with variable penetrance, no single gene has been identified to date, suggesting possible multifactorial or complex inheritance. Furthermore, there is some evidence that photosensitivity may be inherited independently from the many genetic epilepsy syndromes with which it is frequently associated. Although several monographs on photosensitivity have appeared in the past, no multiauthored book on photosensitivity sharing the experiences of multiple clinicians, scientists, and epileptologists from around the world exists, to my knowledge. The authors of this book originate from 20 countries (47 centers) on 5 continents. Previously, Peter Jeavons and Graham Harding from Birmingham wrote monographs on photosensitivity in 1975 and 1994; Newmark and Penry published an extensive review in 1979; and Takahashi from Sendai, Japan, wrote a monograph on pattern stimulation and low-luminance visual stimulation in 2005. In the past quarter century, there have been many environmental changes which have affected visual sensitivity, especially in children and adolescents. These include electronic games, TV with flashing lights, LED lights, discotheques, and most likely also TVs with HD. Pattern sensitivity can also be a problem. On the other hand, there have been tremendous advances in molecular biology, especially with the advent of next generation sequencing, as well as the establishment of various modalities of functional imaging including fMRI-EEG, MEG, TMS, and the analysis of gamma frequencies in the EEG. These ongoing studies are discussed in detail and hopefully will shed further light on the etiology and pathophysiology of photosensitivity.

vii

Foreword

viii

Although photosensitivity is usually known to be associated with generalized epilepsies, photoparoxysmal responses (PPRs) can also occur in focal epilepsies This book has three chapters dealing with this relatively poorly documented phenomenon. The preface is a brief autobiography of the editor, Dr. Kasteleijn-Nolst Trenite, illustrated with photographs of her mentors, students, international collaborators, colleagues, family, and friends. Dr. Kasteleijn details her journey from veterinary student to medical student to a PhD in epilepsy and photosensitivity which laid the foundation of her subsequent career and eventually led to her title of “Queen of Photosensitivity.” The preface illustrates her passion for her chosen work and her skills as a clinician, researcher, meeting organizer, teacher and mentor, as well as an international collaborator, a devoted daughter, wife, mother and grandmother, and a trusted friend. Another innovative feature of the book is the introduction, where Dorothee summarized the main conclusions arising from each part and then proceeded to summarize together with US-based PharmD Dr. Reed the whole in the final chapter with ideas for future research. My late husband Fred Andermann and I met Dorothee early in her career and were very impressed by her great energy, friendship, and intelligence. We continued to meet at various international meetings as well as epilepsy meetings around the globe. In addition to all the science and innovative investigations, there are a number of very practical suggestions for diagnosis and treatment that are very useful for practicing physicians and caregivers, including guidelines for IPSEEG to prevent seizures. Eva Andermann Neurogenetics Unit and Epilepsy Research Group Montreal Neurological Institute, Montreal, QC, Canada Department of Neurology and Neurosurgery McGill University, Montreal, QC, Canada Department of Human Genetics McGill University, Montreal, QC, Canada

Preface

You might wonder why and when my interest in photosensitivity started and how my focused investigation, my “deep-dive,” into the fascinating subject of photosensitivity in epilepsy has developed over time. Having worked evenings and weekends for veterinary surgeon and magician Dr. Winkel during my high school days, I learned to observe pets and to deal with the important bonds between a pet and an owner. At the University of Utrecht, where I switched from veterinary surgery (more dedicated at the time to farming issues) to medicine, lectures by epileptologist Marinus van Heycop ten Ham (known for his research in LaFora disease) were fascinating: he showed videos of seizures from his patients at the epilepsy center Meer & Bosch, de Cruquiushoeve (M&B) in Heemstede, The Netherlands. It was thus no wonder that I (see Fig. 1) applied for a job as epileptologist at the children’s department of this Dutch renowned epilepsy center. M&B gave, at the time (1980s), integral medical care to ~10,000 outpatients and 1000 inpatients for short- and long-stay. The internationally oriented director at that time, Harry Meinardi, president of IBE from 1977 to 1981 and ILAE from 1989 to 1993, appointed Colin D. Binnie, from London, as head of the EEG department (see Fig. 2). Fig. 1  A 25-year-old medical student

ix

x Fig. 2  Colin Binnie in M&B

Fig. 3  New Year’s Eve at home, 1983, with daughter Louise

I soon recognized his great knowledge on epilepsy, in general, and his excellence in doing research utilizing EEG. While I had many ideas about research topics, including photosensitivity, Colin convinced me to choose PhD research on the subject of photosensitivity, an interest he gained in his London years working with among others—especially Arnold Wilkins (known from his work on pattern stimulation). Colin Binnie, Jan Overweg, Jim Rowan, and Jaap Meijer thoroughly taught me the importance of EEG in epilepsy diagnostics and also about the added value of long-term video EEG and pharmacology combined. My clinical and research endeavors were very important to me early on. Then, as in modern times, I recognize that many women in medicine urgently try to find balance between their challenging career and hectic but precious home-life (see Fig. 3): here, I hope to show, by example, that it can be done! I am very proud to say that I had two wonderful children (Louise and Laurens) to care for while pursuing my varied clinical and research interests. For sure, the strong support of my husband, Bart, was and is still crucial all along! In 1986, I received the Young Physician’s award—Gowers Prize at the Golden Jubilee Conference and Northern European Epilepsy Meeting in York (UK) for my self-initiated and performed study on symptoms and signs during intermittent photic stimulation and their relation to seizures in daily life (JNNP, 1987, 50:1546–49). Certainly, receiving such an esteemed award gave me the confidence that I indeed could do clinical research and start answering questions/hypotheses

Preface

Preface

xi Fig. 4  The setting of photic stimulation

Fig. 5  Kobus Willemse (seated left) and Peter Jeavons (seated right) moderate my thesis defense, Utrecht, The Netherlands

I gathered from clinical experience in treating a variety of patients of all ages and any handicaps. Excellent EEG technician Erwin Dekker (see Fig.  4) played an important role in studying photosensitivity. In 1989, I defended my thesis in Utrecht in the presence of child neurologists Jacobus Willemse (my promotor from Utrecht University) and Peter Jeavons from Birmingham—the founding father of photosensitivity in the UK (see Fig. 5). The thesis is published in Acta Neurologica Scandinavica (1989; 125:3–149). From then on, research certainly started to play a very important role in my professional life. I started the foundation of a research department at M&B to focus on the following: 1. Strengthening our collaboration with various national and international universities; among others especially child neurologist Hans Stroink from Erasmus Medical Center, Rotterdam was very interested in detailed studies of his photosensitive patients 2. To establish the working group “Paroxysmal Disorders” of The Netherlands Research Foundation, The Hague, to stimulate collaboration between basic and clinical scientists in epilepsy 3. To organize summer schools for education in epilepsy

xii

At this time, I became intensely involved in the further development of the human “Photosensitivity Model of Epilepsy” as Proof-of-Concept (PoC), Phase IIa research, to accelerate AED development, in close collaboration with colleagues from France, Germany, and USA.  My earlier work in the ‘Photosensitivity Model of Epilepsy’ required that I score large volumes of paper EEG tracings over time (hourly photic stimulation in three eye conditions over a 3-day period). I give tribute to my friend and colleague, Edouard Hirsh, France, as a great proponent for this PoC epilepsy research (see Fig. 6). Realizing that nearly every EEG department had their own photic stimulation procedures, European guidelines for standardized photic stimulation needed to be developed for diagnostic purposes and especially for collaborative research. I therefore organized together with Colin Binnie, Graham Harding, and Arnold Wilkins a workshop in Heemstede on standardization of photic stimulation (see Fig. 7).

Fig. 6  EEGs to read for a Phase II ‘Photosensitivity Model of Epilepsy’ study; Edouard Hirsch

Fig. 7  Workshop in 1998 at M&B, outcome published with all participants: Kasteleijn-­ Nolst Trenite DGA, Binnie CD, Harding GFA, Wilkins A, CovanisT, Eeg-Olofsson O, Goosens L, Henriksen O, Krämer G, Leyten F, Lopes Da Silva FH, Martins Da Silva A, Naquet R, Pedersen B, Ricci S, Rubboli G, Spekreijse H, Waltz S.  Medical technology assessment. Photic stimulation—standardization of screening methods. Neurophysiol Clin 1999; 29:318–324. Several colleagues of our original group (Rubboli G, Martins da Silva A, Wilkins A, Covanis A, Harding G) and, in addition, other IPS knowledgeable colleagues (Seri S, Hirsch E, Parra J, Elia M, Capovilla G, and Stephani U) came forward to update and revise these past 1999 guidelines; the newer 2012 standards can be found at https:// www.ilae.org/files/ilaeGuideline/PhoticStimulation-2012-.1528-1167.2011.03319.pdf or in Epilepsia 2012 Jan; 53(1):16–24

Preface

Preface

xiii Fig. 8  Workshop in 2000 on Visual sensitivity in Aix-en-Provence, France; encircled are from left to right, the key figures: Pierre Genton and Colin Binnie, Alberto Tassinari, Fred Andermann, me, Eva Andermann, Renzo Guerrini, and Michelle Bureau

Over time, I, together with Pierre Genton and Renzo Guerrini (see Fig. 8), organized more international workshops in France and The Netherlands, which led to animated discussions and subsequent publications on visual sensitivity and JME (40% of JME patients are photosensitive). The Aix-en-­ Provence workshop entitled “Visual Sensitivity in the Modern Environment” led to consensus on terminology and classification of clinical and EEG phenomenology in photosensitivity (Epilepsia 2001 May; 42(5):692–701) and key lectures were published in Epilepsia 2004; 45, Supplement 1. An European Consortium on the “Genetic Analysis of Photosensitivity and Visual Sensitive Epilepsies” was started in 2002 in close collaboration with Utrecht University; even today, it is active in dealing with other issues in photosensitivity as well. Together with Bobby Koeleman and Dalila Pinto, we collected many DNA samples in combination with clinical information of photosensitive patients from the practices of Giuseppe Capovilla, Mantova, Italy, Thanos Covanis, Athens, and Bosa Jocic-Jacubi, Nis, Serbia. Finding “a gene” for photosensitivity is far more difficult than expected and taught us that the underlying epilepsy type or syndrome is prominent, as shown nicely in the publications of Dalila Pinto and Carolien de Kovel (de Kovel CG et al. Whole-genome linkage scan for epilepsy-related photosensitivity: a megaanalysis. Epilepsy Res 2010:286–94; D Pinto et  al., Explorative two-locus linkage analysis suggests a multiplicative interaction between the 7q32 and 16p13 myoclonic seizures-related photosensitivity loci. Genet Epidemiol 2007:42–50) I willingly and eagerly accepted invitations to lecture and visit universities all over the world; this undoubtedly strengthened the photosensitivity network (Fig. 9). The Nintendo videogame reports on provocation of seizures led to the sponsoring by Nintendo through the Japanese Epilepsy Foundation of a workshop on ‘Electronic Screen Games and Seizures’ in London (Epilepsia 1999; 40; Supplement 4, co-edited with Binnie and Harding) and an European study on videogames with the collaboration of Italian, Portuguese, and Dutch colleagues (Kasteleijn-Nolst Trenite DGA, Martins da Silva A, Ricci S, Rubboli G, Tassinari CA, Segers JP.  Videogames are exciting. Epileptic Disord 2002: 121–128).

xiv Fig. 9  With Takahashi, Sendai, Japan, known for his work on low luminance red light and dot patterns

Then, I became more and more involved in teaching and doing research with my Italian colleagues through invitations by Alberto Tassinari and Guido Rubboli in Bologna and by Raffaele Canger from Milano to regularly lecture in his Gargnano masterclass school. Invited by child neurologist, Maurizio Elia, from the Oasi Institute, Troina, Sicily, we organized a workshop on “Reflex Epilepsy,” including, of course, photosensitivity, in 2005. Very important and esteemed speakers included the above-mentioned Italian colleagues as well as Bobby Naquet (France), Heinz Gregor Wieser (Switzerland), Dieter Janz (Germany), and Benjamin Zifkin (Canada). Invitations by Mario Brinciotti (known for his research on pattern) and especially Stefano Ricci (see Fig.  7, second from left) led me to Rome. Unfortunately, Stefano Ricci passed away. It was his pupil, Marta Piccioli (see Fig.  11a), who asked for my help to finish Stefano’s paper on videogames and make her neurology residency at Sapienza University a success. Marta and I worked on research data from Bambino Gesù (including holidays, since it was fun!), together with the head of Child Neurology, Federico Vigevano (later also nice collaboration with Nicola Specchio). These efforts encouraged me to apply for an European Grant in collaboration with my Roman colleagues. With great joy I indeed received the prestigious European Grant within the FP6 EU Research Program to become one of the few “Marie Curie Excellence Chairs.” I was appointed at the Neurology Department (head: Cesare Fieschi) of Sapienza University at St Andrea Hospital, Rome, Italy from 2006 to 2009 (see Fig.  10). This grant (MEXC-CT-2005-24224: Visual Sensitivity) comprised two main elements: (1) exchange of knowledge and training of advanced and other medics, paramedics, and lay people and (2) research.

Preface

Preface

xv

Fig. 10  Driving from my apartment at the Via Flaminia Nuova to my work in St. Andrea Hospital, Sapienza University, Rome, Italy, 2006

Fig. 11 (a) Marta Piccioli, (b) Laura Cantonetti at work with me, (c) Maria Pia Villa and Pasquale Parisi

This pivotal Marie Curie Grant successfully promoted further research on photosensitivity, culminating in: • 18 peer-reviewed articles plus 3 book chapters • 23 abstracts for posters and presentations at Italian and international congresses • education and dissemination of knowledge about photosensitivity and epilepsy to the public at large through the Italian press, an Italian videogame software editing organization, including lectures for lay people and two workshops in Rome (one together with Alberto Spalice with contribution of pharmacologist Janet Mifsud from Malta, vice president of the IBE) and another on visually induced seizures in 2008 with Carla Buttinelli. My PhD students Marta Piccioli (adult neurology) and Laura Cantonetti (child neurology) and pediatricians Pasquale Parisi and Maria Pia Villa were all instrumental to the success of the EU grant (see Fig.  11a, b, c). Many young colleagues are inspired and active, and for sure, our wonderful collaboration on photosensitivity, epilepsy, and migraine is ongoing. Neurologists Luiz Barreto Silva (Teofilo Otoni, Brazil) and Paul Timmings (Hamilton, New Zealand) crossed my path at international epilepsy conferences, and thanks to regular (email) contact, they both received their PhD degree at the universities of San Paulo and Auckland, respectively, on studies on photosensitivity.

xvi

Pleasant and fruitful collaboration with Ronald C. Reed started in 2005, while he worked in 2005 at Abbott Laboratories, Neuroscience Research and Development, Chicago (see Fig. 12), in a photosensitivity study with IV VPA (performed at Vanderbilt University, Nashville, with Bassel Abou-Khalil). Since then, we have undertaken many AED-related studies (recently at St. Louis with William Rosenfeld) and scientific university projects. Thanks to lectures and a very lively masterclass in Moscow and ­especially a wellorganized nationwide inventory of knowledge and attitude of neurologists/pediatricians toward photosensitivity, all organized by child neurologist Kira Voronkova from Moscow (see Fig. 13), it became more clear what future paths are necessary to give practicing colleagues the information they need. I also have had wonderful collaboration with researchers conducting EEG studies in photosensitive animals: baboon studies of Akos Szabo, San Antonio, Texas; Rhodesian Ridgeback dogs of Gerhard Kluger, Vogtareuth, Germany; and rats of Daniel Uhlrich, Madison, Wisconsin, USA (see Fig. 14). Overall, my international projects, collaboration, and friendships still continue today. I am currently academically appointed in the Department of Fig. 12  Ronald C. Reed

Fig. 13  Kira Voronkova

Fig. 14  Photosensitive animals studied under the sensitive care of colleagues Szabo, Kluger and Uhlrich

Preface

Preface

xvii Fig. 15  This fulfilling life with wonderful research and colleagues keeps me young-at-heart and smiling

Neurosurgery and Epilepsy, Utrecht University. I wish to acknowledge Peter van Rijen, Frans Leijten, and Cyril Ferrier, who have all helped me to further form an integral view on epilepsy; more importantly, they have helped and encouraged me to support young scientists (especially Dora Hermes with her work on gamma waves and patterns sensitivity) and young physicians and technicians to experience the special role photosensitivity can play in deciphering epilepsy (Fig. 15). I am grateful for the wonderful contributions of so many esteemed colleagues to this book, with whom I worked together and am confident that this book will further stimulate interest and research in this specific phenomenon of epileptiform EEG discharges that can be evoked by visual stimuli to the benefit of all patients with epilepsy. And for those who might wonder if I myself are photosensitive, I have been exposed to so many flashes and striped patterns over the years, that I know, confirmed via EEG, that I do not have (photosensitive) epilepsy. Utrecht, The Netherlands

Dorothee Kasteleijn-Nolst Trenite

Introduction

 ommentary and Insight on the Importance C of the Respective Chapters, as Stated in This Book Titled: The Importance of Photosensitivity for Epilepsy What can we look forward to in this new book? Each chapter provides a sentinel summary of past knowledge plus an abundance of new information concerning each topic. The chapters in this book have been grouped into various themed sections, for which I have provided both commentary and insight, herein, plus, I have hopefully provided a similar keen annotation for each individual chapter, written by experts, as well.

 verview of Part I: Has Photosensitivity Changed Over O the Years? Yes, photosensitivity has changed over the years: • Provocative factors in our indoor and outdoor environment have increased enormously and became diverse. Recognizing sensitivity for a particular visual stimulus has thus become much more difficult. • Home video and cellphone pictures of suspected provocative situations and devices are helpful in diagnosing photosensitive epilepsy. • Deep red monochromatic flashing lights are being used in many modern videogames, advertisements, and cartoons and have been proven to be extremely provocative. • Routine IPS methodology is less rigorously performed with technically flawed photic stimulators. Many physicians consider thus visual sensitivity as a condition that has disappeared or is less relevant. • Instead of classifying photosensitivity as a “stand-alone” entity in epilepsy and pathophysiology, it is nowadays more considered as an integral part of the epilepsies. • The epilepsy photosensitivity gene has not yet been discovered, but many candidate genes of syndromes and epilepsies that are connected with PPR have been found.

xix

Short title Epidemiology

Provocative factors

History

Photosensitivity within the classification systems

Genetics

Chapter # 1

2

3

4

5

Corresponding author Editor’s commentary Detailed descriptions of methodology and outcome of the various studies performed in healthy and epilepsy populations Barreto da Silva since 1949 are given. In nearly every study, a female preponderance is found in those sensitive to intermittent photic stimulation while this is not found in those with sensitivity to striped patterns, regardless the methodology used. Pattern sensitivity is, to date, never shown in healthy subjects; photosensitivity seems to be a trait that can stay sub-clinically in healthy children with normal background EEG. See also Chap. 7 on prognosis. Striano Visual sensitivity, being the most important reflex type of epilepsy, typically has recognizable provocative factors in daily life. Best known for its seizure provocation are these situations: flickering sunlight, disco lights, electronic screens, and videogames; patterns and fluorescent lighting are much less known for their provocation. New, potentially provocative devices (e.g., curved, HD television screens and high-intensity LED lamps) need to still be investigated in the EEG laboratory. In this chapter, special emphasis is put on the outcomes of EEG studies in photosensitive patients of the different visual stimuli and its meaning for understanding epilepsy in general. Genton Ancient medical traditions recognized the influence of natural visual stimuli as a seizure-provoking factor. In the twentieth century, EEG technology made it possible to “visualize” this sensitivity: in Europe, the USA, and South Africa, many famous epileptologists built (simple) photic stimulators and studied the effect of flashing lights on brain waves in epileptic and psychiatric patients. Colleagues in Japan and India followed soon afterwards. It is fascinating to learn about the origin and development of photic stimulation before it was implemented as a routine method in EEG diagnostics. See also Chaps. 18 and 19 for the historical role of animal research. Appleton In the latest ILAE 2017 classification, photosensitivity-related items are found only in focal non-motor onset (sensory) and generalized non-motor (eyelid myoclonia, EMA) seizure types. EMA is one of the most debated epilepsy types; it is still unclear if it should belong to the absence or myoclonic types of epilepsy. This very easy-to-­read chapter describes the place of photosensitivity in historical classifications, goes into detail in its position within the various syndromes, and concludes that, at this moment, a separate classification of photosensitivity is unnecessary and impracticable. However, in the editor’s opinion and as we discover more, it is important to have a specific axis for those who are photosensitive—a JME patient with a PPR needs other advice than a non-photosensitive JME patient. Bebek Although it has never been doubted that PPR is a genetic trait, it is yet not clear which genes are involved. Some genes have been discovered to play a role in a variety of syndromes connected with PPR. Further research for PPR genes is necessary; this chapter gives a complete overview of our current knowledge and understanding of PPR genetics and is valuable for clinicians and researchers alike.

xx Introduction

Introduction

xxi

 verview of Part II: Does Photosensitivity Matter; Clinical O Relevance? Yes, photosensitivity clearly does matter: • In particular, when PPRs, being either generalized or focal, are accompagnied with (subtle) clinical symptoms during IPS testing, the likelihood that the patient has epileptic seizures in daily life is very high; thorough clinical history taking is important. • Insight into their own clinical symptoms and signs during PPR helps patients to detect their individual provocative factors in daily life and thus learn to avoid these. • When photosensitive patients unwittingly encounter visual stimuli, e.g., flashing programs on TV, sunlight, or LED lamps in tunnels during driving, immediate covering of one eye with their hand prevents a seizure. Every photosensitive patient should get this advice. • Measuring the photosensitivity ranges as biomarker of sensitivity helps to determine the risk of seizures at different ages and to monitor efficacy of antiepileptic drug treatment. • The highest prevalence of photosensitivity, as well as the highest sensitivity (ranges), are seen in adolescent females: girls not needing treatment yet might need more protection some years later. Clinical follow-up with IPS-­ EEG (photosensitivity ranges) is necessary. • If withdrawal of anti-epileptic drug (AED) is intended in (seizure free) photosensitive patients, regular IPS-EEG before, during, and after complete withdrawal can reveal that the photosensitivity returns or increases. Re-installment of the AED regimen can thus prevent occurrence of GTCS or even status (personal data). • PPR at an early age (e.g., in Dravet syndrome) gives a worse prognosis in epilepsy in general. Interaction of different underlying mutated genes might be the cause. • PPR certainly occurs also in focal epilepsies, and therefore, the epilepsy of a PPR patient should not be automatically classified as generalized. Classification has its implications for further diagnostic workup, prognosis, and treatment. • Photosensitive children and adults (even those with generalized epilepsy) can have a visual aura and headache complaints; this should not be mistaken for migraine. • Discomfort to flickering lights, striped patterns, and TV screens is reported not only in patients with photosensitive epilepsy but also in those with headache disorders, brain tumor, panic disorders, and after brain trauma.

Short title Correlation EEG and clinic

Prognosis

Special syndromes

Chapter # 6

7

8

Corresponding author Editor’s commentary Capovilla Photoparoxysmal EEG responses (PPR) can be focal (Waltz grade 1 and 2, usually over the parieto-occipital area of the brain) or generalized (Waltz grade 3 and 4). It is useful to diagnose syndromes and monitor treatment. PPR are found in many different epilepsies, ranging from the catastrophic epilepsies to the benign focal epilepsies. In this chapter in particular, there is an impressive collection of PPR examples with concomitant clinical information. Steinhoff Prognosis is a difficult subject in epilepsy, in general, and even more in photosensitive epilepsy or epilepsy with a PPR. Age, treatment, and underlying epilepsy syndrome/comorbidity play a role. We need standardized and repeated photic stimulation, with the determination of ranges as follow-up study clinically. PPR, as isolated phenomenon, is especially seen in female adolescents and seems to disappear in about 30% around 30 years of age. However, in a recent study in healthy school children, it appeared that one female of the seven PPR-positive children developed later epilepsy: focal epilepsy with a temporal focus (see Chap. 1); thus, it might be that she has inherited traits for temporal epilepsy and PPR and that the interaction caused seizures. A study in children with generalized epilepsy and a PPR suggested that seizure freedom (77%) was independent of disappearance of the PPR (37%). However, the IPS methodology is not clearly described and testing included only the eyes closed condition. It is, in addition, imperative to recognize that while abolition is important, diminishment of photosensitivity ranges is definitely known to reduce the risk of having seizures and could therefore contribute to seizure freedom. An extensive survey is given of the various aspects of prognosis. The case report of a patient, who responded favorably during a controlled Proof-of-­Concept trial to a single oral AED dose, but did not react anymore when in long term steady-state, is intriguing; is this a difference between acute and chronic treatment or lack of compliance in a possibly self-inducing woman? Unfortunately, blood AED levels have not been measured during the EEGs at steady state. Franceschetti PPR occurs in many epilepsy subtypes (10–92%) and is found in patients with chromosomal abnormalities (e.g., Down syndrome) as well. While myoclonic seizures are provoked during IPS, occipital seizures occur as well, dependent on the type of epilepsy it is connected with. In encephalopathic epilepsies of infancy, it is remarkable that the PPR appears to be an early marker of severity, yet is also a transient phenomenon. A nice and comprehensive overview is given of the different aspects of PPR that appear in the various syndromes from infancy to adulthood.

xxii Introduction

Focal epilepsy EEG perspective Focal epilepsy Clinical perspective

Various disease states

What to learn from a patient

10

12

13

11

Focal epilepsy General overview

9

Timmings

Parisi

Jocic-Jakubi

Martins da Silva

Brandt

Photosensitivity can be found in up to 20% of focal epilepsies, the most frequent type being occipital lobe epilepsy. In the recent review by Kasteleijn et al. on focal epilepsy and PPR (Epil Res. 2017; 133: 113–120), it was also found that “focal epilepsy” AEDs are effective both in the “Human Photosensitivity Model of Epilepsy” and in real life in photosensitive patients. A clear overview is given of the position of photosensitivity in relation with focalities within the new classification of epilepsies. See also Chap. 6 and the following Chaps. 10 and 11. Modern techniques help in finding evidence of a local origin of the photo-paroxysmal EEG response, regardless the type of epilepsy it coincides with. It becomes also more and more clear that, even in generalized epilepsies, focal signs such as visual aura are not uncommon. Read also more about the use of gamma waves in photosensitivity research in Chap. 17! The prevalence of photosensitivity is not only age dependent (higher in younger age groups), but also the likelihood of finding photosensitivity in focal epilepsies is age dependent (higher in adults). Occipital seizures, especially present in children, are different: thanks to the slow generalization of the occipital discharges focal clinical features are much more easily recognized. In this comprehensive chapter, special focus is placed on the various occipital epilepsies and their overlap with generalized epilepsies. Few studies have addressed this subject. Some isolated cases have been published where clinicians encounter a combination of a specific disease with a PPR by coincidence. Links between the various disease states and epileptic photosensitivity exist however; for example, discomfort to bright (intermittent) light, striped patterns, and TV screens is reported not only in patients with photosensitive epilepsy but also in those with headache disorders, brain tumor, panic disorders, etc. High alpha EEG power and photic driving might be the reason of this discomfort. In posttraumatic epilepsy, both photophobia and PPR have been shown. Parisi and colleagues give us a fascinating view on the pathophysiological pathways that are involved in a hyperexcitable visual cortex. Patients can recognize potentially provocative stimuli in their environment, such as use of faulty LED lighting. Fortunately, avoidance of triggers can be helpful in managing the condition. Measuring the photosensitivity ranges as biomarker of sensitivity helps to determine the risk of seizures at different ages and to monitor efficacy of antiepileptic drug treatment. Critical analyses of several studies on AED effect on PPR are given.

Introduction xxiii

xxiv

 verview of Part III: Abnormal Electroencephalographic O Response to Photic Stimulation in Humans and Animals Studying EEG responses to IPS in humans and animals has taught us the following: • Distinction must be made between the diverse PPR waveforms with its various locations of onset of PPR and physiological normal evoked responses. • Gamma oscillations seem to be highly correlated to the provocativeness of visual stimuli. • The connections between the occipital cortex and motor brain areas are strong and explain why clinical signs during PPR are, in the majority of cases, of myoclonic nature. • Cortical and sub-cortical brain connections have been shown during a PPR. A PPR is thus part of an epileptic brain network and can help elucidate the very nature of epilepsy. • Three animal species (baboon, chicken, and dog) are known with naturally occurring photosensitivity: this raises hypotheses about natural selection (advantage/disadvantage on being photosensitive) and gives clues on pathophysiology and genetic transmission. • Differences in EEG reaction to visual stimuli are noticed in different rat strains: albino rats have more and larger photically induced after discharges than pigmented rats. • Sprague Dawley rats can be photo-sensitized with extreme flashing, while baboons with a PPR decrease their sensitivity on repeated stimulation. Both these observations are however not seen in humans. • Genetic research in homozygous photosensitive Ridgebacks (dogs) gave us the PPR-connected gene DIRAS1.

Introduction

Motor manifestations

The basics

Gamma oscillations

What can we learn from animals?

Photo­ sensitivity in rats

15

16

17

18

19

van Luijtelaar

Szabó

Avanzini

Koepp

Rubboli

Guerrini

How to interpret EEG results?

14

Photoparoxysmal responses are often considered to be only generalized, rhythmical, and consisting of spike and waves: this interpretation is incorrect, because PPR can consist of different waveforms and localization, just as in focal epilepsy. Furthermore, spikes, one of the variations in PPR, should not be confused with the normal visual evoked responses that are phase-locked to the flash. Sleep deprivation and spontaneous sleep thereafter have an important impact on occurrence of PPR. PPR is part of a genetic trait or an epileptic disease and nice examples are given of PPR in different epilepsy syndromes. There is evidently a strong connection between the occipital cortex and the motor regions as seen in the clinical symptomatology of the majority of photosensitive epilepsies and in its explicit form in eyelid myoclonia with absence seizures. A thorough, thoughtful, and very interesting insight is given in the various aspects of eyelid myoclonia, including self-induction and pathophysiological mechanisms. The different functional studies show altered connections within networks in photosensitive patients and during PPR: cortico-­cortical, including visuo-motor, and cortico-subcortico-cortical connections (via thalamus and callosum) are involved. Excitability at rest and during a PPR might be key in understanding basic underlying mechanisms of photosensitivity. The latest developments in unraveling the pathophysiology of the PPR are given in this important chapter. Gamma oscillations (30–100 Hz) have been studied more intensely since the past two decades when advanced digital EEG and MEG software became available. In this fascinating chapter, hypotheses are given about how various provocative visual stimuli can inhibit, destabilize, or synchronize the circuits in human visual cortex. In other words, what triggers the PPR? Photosensitivity (clinical history and PPR) has been studied extensively in three natural animal species: Papio Papio and other baboon subspecies, Fayoumi chicken, and lately Rhodesian Ridgeback and other dog species. Although there are similarities to human photosensitivity (familial congregation of PPR, Juvenile Myoclonic Epilepsy or Progressive Myoclonic Epilepsy phenotype), there are also differences: response to anti-­epileptic drugs (AEDs) is not exactly similar, and repeated IPS can reduce photosensitivity in the baboon. Genetic research has been successful: the new gene DIRAS1 was found mutated in homozygous Ridgebacks. This chapter gives an excellent overview of clinical, neuro-physiological, and neuro-pathological outcomes of animal studies, thus enriching our knowledge on the photosensitivity trait. Similar to human research, there is an especially great variability in latency and amplitude of the early components of visual evoked potentials (VEPs) found in rats due to different methodologies. Also, strain differences are seen: albino rats have more and larger photically induced after discharges (PhADs) than pigmented rats. The PhADs are of special interest because they are enhanced by (a) quiet animal behavior, (b) the proconvulsive agent PTZ, and (c) GABA antagonists; alternatively, they are suppressed by the anti-seizure drugs ESM, VPA, DZP, that are effective in human photosensitivity as well. In the genetic absence rats, VEPs can be elicited, but they become much more aroused by photic stimulation than humans with strong suppressive effect on the spike and wave discharges (SWDs) as a result. To date, no PPR has been recorded in rats, although Uhlrich et al. (J Neurophysiol. 2005; 94: 3925–37) managed to sensitize rats gradually to flicker with chronic IPS. Studies mentioned in this very informative and absorbing chapter gives us insight into pathways of photosensitivity and SWDs.

Corresponding author Editor’s commentary

Chapter # Short title

Introduction xxv

xxvi

 verview of Part IV: Peculiarities of Photosensitivity O in Diagnosis and Treatment Photosensitive patients do indeed have their peculiarities: • Prevalence rates of PPR differ among ethnicities, indicating that there is an important genetic factor involved. • Very specific for photosensitivity is a systematic overrepresentation of females (2:1) in a healthy normal population or in epilepsy. • In adolescence female preponderance in PPR-positives is maximally with also the biggest photosensitivity ranges in the EEG, suggesting an important role of X-linked genes and sex hormones. • Dravet syndrome children show a peculiar type of photosensitivity: PPRs occur already at the very start of the disease and in time even before the spontaneous EEG discharges occur. Furthermore, the photosensitivity comes and goes, which cannot be explained easily by (changes in) anti-­ epileptic drug (ASM) treatment. • Dravet syndrome patients are more often pattern sensitive and self-­ inducers of seizures (“sunflower syndrome”). • PPR can be used as a biomarker for efficacy testing of AEDs, for all types of epilepsy. This has led to the human “Phase IIa Photosensitivity Model in Epilepsy” proof-of-concept study for novel potential AED/ASM development. • Higher prevalence rates of epilepsy in general are found in the developing countries; it is possible that head trauma, perinatal injury, and CNS infections, all more seen in those countries, could result in a higher incidence of photosensitive epilepsy than expected.

Introduction

Short title Genetic (ethnic) differences

Gender differences

Age differences

Dravet syndrome

The Human Photosensitivity Model

Identification of geographic

Chapter # 20

21

22

23

24

25

Mifsud

Reed

Berten

Seri

Delanty

Corresponding author Shiraishi

Editor’s commentary Typical for photosensitivity, there are clear differences in prevalence of PPR with or without epilepsy among multiple nationalities and ethnicities. Based on a variety of studies, hypotheses to explain these differences are being discussed. A very interesting chapter! In nearly all epilepsy syndromes, patients with a PPR will show female preponderance (exceptions are childhood absence epilepsy and the progressive encephalopathies). Also, the likelihood of having epileptic seizures is greater in women with a PPR. More research needs to be done to elucidate the role of sex hormones and X-linked genes in photosensitivity. This chapter provides an excellent starting point! Photosensitivity, in general, is most prominent at childhood and adolescence and the question thus arises: “What role does maturation of the visual system and related networks play?” However, photosensitivity is also found at other ages and is dependent on the epilepsy type it is connected with. This very interesting chapter argues both type of hypotheses. A genetic etiology of Dravet syndrome (DS) is known since 2001 (SCN1A gene), and many phenotype– genotype correlations have been made. Early photosensitivity, often combined with pattern sensitivity and self-induction, is considered part of DS. Another typical provocative factor is elevation of body temperature. Rigorous analysis of clinical and EEG data of 58 patients with DS and comparison with available literature are described in this insightful chapter: it especially shows discrepancies in study results due to selection bias, IPS methodology, and differences in PPR definition. The PPR can be used as a biomarker for AED pharmacotherapeutic studies. Over the years, this Proof-ofConcept principle has led to a standardized human Phase IIa Photosensitivity Model in Epilepsy (“PMoE”) with its successful detection of preliminary efficacy of single oral doses of new AEDs. If rapidity of brain entry or impact of small pharmacokinetic changes (both via IV infusions) need to be evaluated, adaptation of methodology is imperative. Such trial adaptations are described and explained with great knowledge and detail. In the “early days,” study sites were limited to the UK, USA, and France (see Chap. 3 on history). The authors of this chapter have documented, that studies on photosensitivity have been additionally performed in many other sites in European countries, South America and Asia. Interest in photosensitivity has thus grown, which is reflected also in the diverse geographical background of the authors in this book. A plea is made for further information on photosensitivity in developing countries.

Introduction xxvii

xxviii

 verview of Part V: How to Approach the Photosensitive O Patient, the Caregiver, and the Surrounding Photosensitive patients need the following: • First of all, a good clinical history from caregiver and patient alike is instrumental for a proper diagnosis and a way to help the patient in ­deciding if avoidance is sufficient or that anti-epileptic drug (AED) treatment is necessary. • A proper video-EEG with IPS (and provocative videogame), according to the guidelines, gives maximal information with a minimum of risk of provoking a GTCS. • A combination of history and EEG allows an individual approach to optimally advise the photosensitive patient concerning avoidance of visual stimuli and/or use of different types of AED. • Physicians are in need of clear protocols and flowcharts concerning detection and handling of photosensitivity. • Patients need to be warned for new technologies (e.g., virtual reality [VR] glasses and high-definition screens [HD TV]) that could worsen their photosensitivity. • Architects who are involved in building constructions and interiors need to get information from their professional organizations how to diminish provocative visual stimuli that can provoke seizures.

Introduction

Short title Optimizing the patient’s history

Maximizing EEG methodology

Safety of EEG methodology

Treatment and prevention: When?

Chapter # 26

27

28

29

Yacubian

Whitehead

Abou-Khalil

Corresponding author Brinciotti

Editor’s commentary In general, taking a good clinical history is very important, but certainly is the case for the diagnosis of potential visually induced seizures. The circumstances under which seizures happen need to be “dissected” with the help of cameras and drawings of perceived visual aura. Self-induction needs a special approach. The authors give a very clear, concise, and up-to-date overview of environmental provocative visual stimuli and stress that also the type of concomitant epilepsy/ syndrome must be taken into account. Proper EEG diagnostics confirm a clinical history of seizures that are (possibly) provoked by visual stimuli. It can also provide a measure of photosensitivity that predicts liability to seizures in daily life and allows follow-up of AED treatment effect. During AED withdrawal, PPR ranges can be monitored to predict likelihood of re-occurrence of seizures. But how do we best register an EEG that is maximally informative? In this chapter, the best methodology is simple and explained in detail with many examples, all according to the guidelines of the professional organizations IFCN, ACNS, and ILAE (European guidelines). EEG technicians are often reluctant to perform photic stimulation routinely; they never seem to forget a generalized tonic-clonic seizure that occurred unexpectedly during or shortly after intermittent photic stimulation of a patient. Studies, however, show a very low incidence rate of GTCS (10% had abnormal background EEG recordings. Mundy-Castle [18] examined the effect of age on the effect of IPS on the EEG in normal individuals, 154 with a median age of 22 years, and 40 with a median age of 75  years. The Scaphony photo-stimulator was placed 15 cm in front of the eyes, stimulation frequencies were used in increasing and decreasing order from 3.5 to 100 Hz, with eyes closed and open. Abnormal responses (spike- or polyspike-wave complexes) were found in six younger (all experiencing either a myoclonic or clonic seizure), and one older individual (total 4.5%). Mundy-Castle noted an association between the presence of alpha variants and sensations provoked by IPS. Comment: PPRs appear to be more common in younger adult age groups. Buchtal and Lennox [19] evaluated the effect of the pro-convulsant pentylenetetrazol on the response to IPS in 682 normal, male, air force recruits, to assess their tendency to seize. The photo-stimulator was placed 5 cm in front of the closed eyes and IPS was undertaken with frequencies of 1–60 Hz. The authors defined abnormal responses as spikes, sharp waves, paroxysms of slow waves and spike-wave complexes with amplitudes more than 100  μV.  In those with background EEG patterns that were normal, discrete abnormal, suspicious paroxysmal and paroxysmal abnormal responses to IPS were seen in 1.4, 5.1, 10.7, 10.4, and 100% of individuals, respectively. Individuals with a normal waking EEG were also compared to 100 patients with tonic-clonic epilepsy; abnormal responses to IPS were identified in 1.4 of the first, and in 13.5% of the second group. Comment: Background EEG abnormalities and particularly spontaneous epileptiform discharges increase the likelihood of the individual being photosensitive. The percentage of abnormalities evoked by IPS is much higher due to the use of the pro-convulsant, pentylenetetrazol.

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

Gastaut et al. [20], using the same stimulator as Walter, investigated IPS evoked slow waves with predominance over the parieto-­ occipital areas in 500 normal subjects. No subject was found to have spike-wave complexes, but 1.3% demonstrated occipital slow waves. Comment: Gastaut and colleagues pointed out that the onset of the PPR lies in the parieto-­ occipital area. Stein et al. [21] studied IPS responses in 100 healthy adults with no history of a neurological disorder. A Schwarzer stroboscope placed at 30–40 cm from their closed eyes produced intermittent light flashes of 10 s duration and similar intervals at frequencies between 2 and 25  Hz. Two adults had a PPR. Comment: Although they made an attempt to study adults without any trace of neurological disease, 2% proved to be photosensitive. Further studies (see below) involved candidates with apparent optimal physical and mental health that underwent an EEG prior to recruitment for flight-training. A longitudinal study was undertaken in 13,658 candidates for aircrew training in the UK to assess the frequency of PPR and how many reported any neurological symptoms (Gregory et al.) [22]. Individuals were aged 17–25  years, with no relevant past medical history, no seizures since the age of 5 years, receiving no prescribed medication and with a normal physical examination. Abnormal responses to IPS were defined as: polyspike- or spike-wave complexes and irrespective of finishing before, during or after IPS. Abnormal responses were seen in 0.32% of this population, mostly provoked by IPS at between 15 and 25 Hz. In the USA, Jabbari et  al. [23] studied 100 young male active duty soldiers (18–45, mean 34 years) after partial night sleep deprivation (3 h of sleep). All were carefully screened for any medical condition and all underwent brain magnetic resonance imaging (MRI). The EEG showed no spontaneous epileptiform discharges. A Grass photo-stimulator 22 at level 8 was used but there was no description of the method of IPS.  No abnormalities were reported other than occasional small sharp spikes.

5

1.2.1.1 In Summary Although different photic stimulators and methods (distance to the lamp, eyes closed or open and closed, duration of stimulation, interpretation of evoked waveforms, partial sleep deprivation) have been used, between 0 and 2% of adults with normal EEG backgrounds and no clinical history of neurological disorders will show a PPR.

1.2.2 S  tudies of IPS in Normal Children and Adolescents Nekhorocheff [24] was the first to provide information on the prevalence of abnormal responses to IPS in normal children. He studied 54 normal French children aged 3 to approximately 15 years. All were reported to attend mainstream education with no relevant past medical history and with an intelligence quotient (IQ) that was either average or above average using the Binet and Simon intelligence test. IPS lasted up to 12 min and was with the eyes open and closed for between 2 and 3 s. Abnormal responses were defined as paroxysms of slow waves, spikes or spike-wave complexes. Abnormalities were demonstrated in five children (9.25%); one child had experienced a single epileptic seizure in infancy as discovered later after discussing the PPR and another four, two brothers and two sisters, had no relevant previous medical history. Herrlin [25] analysed responses to IPS in 70 normal Swedish children with no previous history of any seizures, aged a few weeks to 15 years and compared these with children with confirmed or possible or probable epilepsy. EEGs were undertaken using a Grass electroencephalograph and with the children awake or asleep. IPS was performed in a dark room using a Scaphony photo-stimulator, placed 10–20 cm in front of the eyes. Stimulation frequencies were 4–100  Hz, with the eyes open and closed and performed over 20  min. Abnormal responses to IPS were defined as generalized slow wave activity, with or without spikes, and with amplitudes of 100– 200 μV, if this was greater than the background activity amplitude. All children had a normal background EEG.  During IPS, one child (aged

6

8 years with haemophilia and no family history of epilepsy) showed generalized spike-wave complexes provoked by an IPS frequency of 10 and 11 Hz. Overall, the prevalence of abnormal responses was only 1.4%. Brandt et  al. [26] studied the abnormal responses to IPS in 120 children (62 girls, 58 boys) aged 1–15 years of age with most attending primary and high schools in Copenhagen (Denmark). None had a history of genuine or suspicious epileptic seizures, history of birth or head trauma or infection of the central nervous system or family history of epilepsy. The EEG was performed with an eight-channel Kaiser electroencephalograph during wakefulness and including hyperventilation in 116 children. IPS was given over 6  min with the Kaiser photo-stimulator placed 20 cm in front of the eyes with them open and closed. The intensity of the light varied from 0.25 to 1 megalux depending on the flash frequency with the lower frequencies delivering the highest intensity. The background EEGs were abnormal in 5.8% of cases. Abnormal responses to IPS were defined as generalized paroxysms and high-amplitude parieto-occipital slow waves that occurred at least twice. Generalized paroxysms were seen in 11.6% and high-amplitude parieto-occipital slow waves were seen in 14.2% of children; twice as many girls showed an abnormal response. Comment: A longer duration of IPS seems to be more provocative and girls are more affected than boys. Doose et al. [27] studying the genetics of photosensitive epilepsy in Germany evaluated responses to IPS in 265 neurologically normal children (136 boys, 129 girls), aged 1–15 years. EEGs were performed in wakefulness, sleep and, when possible, with hyperventilation that lasted two and a half minutes. IPS was carried out in a dark room using a Knott photo-stimulator placed 10–15 cm in front of the eyes and with frequencies ranging from 4 to 20  Hz in increasing or decreasing order and for 30 s at each frequency. Abnormal responses, defined as parieto-occipital slow waves with spikes or generalized spike or polyspike-wave discharges, were found in 6.8% of children (5 males, 13 females). Abnormalities

L. C. B. Silva et al.

were seen in 5.5% of 1- to 5-year-olds, 7.7% of 6- to 10-year-olds and 16.8% of 11- to 16-year-­ olds. EEGs demonstrated spike-wave complexes during wakefulness and hyperventilation in 2.3% of the 18 children. Comment: The duration of stimulation per frequency was longer than in other studies. Adolescents were more likely to show a PPR. The authors suggested their findings indicated a predisposition to generalized seizures. Eeg-Olofsson and his Norwegian group [28] studied the IPS responses of 743 neurologically normal children, aged 1–15  years with no personal or family history of epilepsy and with normal examinations. EEGs were performed in the waking or sleeping (natural or drug-induced) and, where possible, during hyperventilation. IPS was undertaken in 81.4% of children using a Kaiser photo-stimulator, placed 15 cm in front of the eyes and with increasing frequencies at 4, 6, 8, 11, 15, 20 Hz (each frequency for 40 s) and then in descending frequencies 20, 18, 16, 15, 14, 13, 12, 11, 10, 8, 6, 4 Hz (each frequency for 20  s). IPS was discontinued in 4 boys and 13 girls because of “distress” (two girls), epileptiform paroxysms and “distress” (one child) and epileptiform paroxysms in the remaining 14 children. Abnormal responses to IPS were found in 8.3% (50 children: 37 girls, 13 boys) defined as: A (13 children) bilateral discharges of slow waves or spike-wave complexes with amplitude greater than 100 μV; B (25 children) polyphasic slow waves with an initial spike or with bilateral spikes, synchronous, and primarily in the temporo-­occipital regions; C (12 children)—both A and B responses. PPRs were seen predominantly between 6 and 15 years of age; the youngest was aged 3 years. Stimulation frequencies of 11–20 Hz provoked the more abnormal responses. Eeg-Olofsson [29] subsequently used the same technique and criteria in the analysis of responses to IPS in a study of 185 normal adolescents (94 girls), aged 16–21 years. Abnormal responses to IPS were seen in 2.7% of adolescents (four females and one male, aged 17–21 years) and at a frequency of 8–20 Hz. All complained of uncomfortable sensations during IPS.

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

Comment: IPS is most effective between 11 and 20 Hz (although it is important to note that the study did not use frequencies higher than 20  Hz) and provoked uncomfortable sensations. Doose and Gerken [30] studied 662 (329 females) children with normal development aged 1–16 years. IPS was performed using the Knott photo-stimulator placed 10 or 15 cm in front of the eyes delivering ascending or descending frequencies from 4 to 20  Hz, with each frequency lasting 30  s. The authors defined abnormal responses to IPS as four types: I.  Biphasic parieto-­ occipital slow waves with spikes; II.  Generalized spikes with slow waves; III.  Occipital spikes; IV.  Bilateral synchronous spike-wave complexes. They found an abnormal response in 7.6% of children, and more commonly in girls. Abnormal responses were seen in 16% of children aged 1–6 years, 56% of children aged 7–12  years and 28% of children aged 13–16 years. The individual abnormal responses (I, II, III and IV) were seen in 40.8%, 16.3%, 4.1% and 38.8% of children, respectively. The type IV response occurred most frequently in the 1- to 8-year-old group and the type I response was more frequent in those aged 8  years and above. Comment: The highest likelihood of finding a PPR is in the age group 7–12 years. Klepel et  al. [31] analysed the EEG during IPS in 330 children (173 females) aged 4–14  years of age. All had normal birth and development, no previous or current neurological or behavioural disorders, not taking any medication and with normal neurological and mental examinations. There was no gender difference across age and educational ability. A Schwarzer BBK 53 photo-stimulator was used (flashing between 2 and 40  Hz) at a distance of 25  cm from closed eyes. The duration of IPS was 5 min but less if there was a PPR. Abnormal responses were defined as focal or generalized spike-wave or polyspike-wave complexes; these were seen in 24 (7.2%) of the children, and more frequently in girls. All 24 children showed generalized or focal spikes during a waking EEG, some during hyperventilation.

7

Comment: Even though their criteria were very strict, a high prevalence of a PPR of 7.2% was found. In addition, all children showed spontaneous generalized or focal spike (epileptiform) discharges. Fonseca [32] studied the EEG of 185 children from 4 to 8 years old and classified as normal according to the criteria of Eeg-Olofsson and analysed the IPS. A Berger photo-stimulator was placed 15 cm in front of the eyes and with increasing (4, 6, 8, 10, 15, 20 and 24 Hz) and decreasing frequencies of 16, 14, 12, 11, 9, 7 and 5 Hz. The eyes remained closed during the stimulation period of 10  s for each frequency; the intervals between stimulations were the same. The authors scored the following EEG responses to IPS: (1) photic driving (in 83.3%); (2) increase of slow waves not synchronous to the stimulation frequency (in 16.2%) and (3) slow wave paroxysms spikes, sharp waves or spike-waves complexes, either focal or bilateral or synchronous diffuse PPR (in 3.8%). Comment: This study only used IPS with the eyes shut, which might have increased especially slow wave paroxysms. Papatheophilou and Turland [33] studied the EEGs of 223 boys living in Birmingham UK, a representative sample of normal school boys aged between 12 and 16 years—“the age in between”. The study was restricted to boys to exclude the possible effect of hormonal variations.  A photo-stimulator SLE CPSA was used with a grid at intensity 2 (0.12  J/flash). In all instances, the photo-stimulator was placed 30 cm in front of the patient’s eyes with the patient being instructed to look at the centre of the lamp. Each burst of IPS was given for approximately 2  s. IPS was discontinued as soon as a PPR occurred to minimize the risk of inducing a seizure. Three boys, aged 12, 14 and 15  years showed generalized polyspike waves during photic stimulation (1.3% prevalence) mainly with eyes open and with flash rates between 15 and 50  Hz. They all had spontaneous asymmetrical discharges in the resting record and during hyperventilation. Closing one eye prevented the PPR.  Two of them experienced recurrent headaches and fainting while watching television, the

L. C. B. Silva et al.

8

other had migraine and one faintness at school at the age of 8  years. Two had birth-related problems (preterm/low weight, cyanosis/developmental delay, respectively). Comment: A grid in front of the stimulator produces a flashing pattern and increases the likelihood of a PPR. In this study, the presence of a grid seemed to compensate for the low intensity of the photo-stimulator. Interesting is the finding that closing one eye can prevent a PPR. Silva [34, 35] selected randomly 909 of all 24,338 students aged 6–18  years living in the urban area of Teófilo Otoni, Brazil and stratified them by age, gender and type of school. Eventually 510 (see Fig.  1.1) children and adolescents met the following criteria: 1. Normal pregnancy, birth and psychomotor development.

2. No history of un-classified paroxysmal episodes or epileptic seizures (282, 11.7%), head trauma with loss of consciousness, medical, neurological or behaviour abnormalities (including encopresis and enuresis) after the age of 4  years, sleep disturbance, learning difficulties, taking medication or recreational drugs or a family history epilepsy in first-­ degree relatives. 3. Normal physical, ophthalmological and neurological exams. 4. Siblings of students were excluded. A clinical history was taken including the following psychosocial issues: how much television they watched, whether they played video games and for how long, used a computer, attended discotheques and whether they had experienced any discomfort in specific situations (looking at the

60

50

Students(number)

40

30

20

gender

10

male 0

female 6

7

8

9

10

11

12

13

14

15

16

17

18

age(years)

Fig. 1.1  Distribution of selected individuals according to gender and age, Teófilo Otoni, 2001–2002

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

sun through trees or looking at striped clothes, televisions, computers and discotheques). EEGs were performed using the EMSA Braintech 240 machine. Individuals were in the sitting position with first two and a half minutes each with the eyes open and closed to identify any spontaneous epileptiform discharges. Hyperventilation was undertaken for 3 min, in all individuals. IPS was performed with the Grass 33-plus photo-stimulator, without metallic grid, delivering stimuli between 1 and 60  Hz of 0.36  J (intensity number 4). The subjects were placed at a distance of 25  cm of the lamp (See Fig. 1.2). The normal luminance in the area of the eyes was 90  lumens/m2. Ascending and descending flash frequencies were used at 2, 4, 8, 10, 13, 15, 18 and 20 Hz and 60, 50, 40, 30, 25 and 23  Hz. For each frequency IPS was done with the eyes open during 10 s and then with the eyes closed for another 10 s. IPS was then suspended for 10 s during which the individual’s eyes remained open. In case of occurrence of a PPR in posterior regions or in a more generalized distribution, IPS was stopped to avoid inducing an epileptic seizure. If the PPR had occurred in the ascending order of flash

9

Fig. 1.2  Set-up during IPS

frequencies, the IPS was interrupted and restarted in descending order. Spontaneous and hyperventilation-evoked epileptiform activity (in the same children) occurred in eight subjects (1.6%); this was focal, predominantly involving the right side and becoming more generalized in 3. PPRs were seen in seven subjects (1.4%): six girls and one boy: 18 times with eyes open, 13 times with closure of the eyes and 4 times with eyes closed (Table 1.1). Examples of the PPR of all seven patients are given below:

Table 1.1  Clinical and EEG data during IPS with PPR localization and lower and upper limits of flash frequency in seven subjects with a PPR Subjects 1 2 3 4 5 6 7

Sex, age M, 7 years F, 8 years F, 8 years F, 9 years F, 10 years F, 11 years F, 15 years

Clinical history No Epilepsy sec degree Epilepsy sec degree Mother addicted No Epilepsy sec degree No

Localisation of PPR gen occ and gen occ and gen gen gen occ and gen occ and gen

Lower limit 18 8 13 8 18 8 13

Upper limit ? 30 40 60 30 30 60

Complaints No Pain eyes Headache Dizziness No No Seeing stars

10

Patient # 1:  Generalized PPR at 18 Hz eye closure

L. C. B. Silva et al.

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

Patient # 2:  PPR with occipital origin and spreading at 30 Hz eye closure

11

12

Patient # 3:  PPR with occipital origin and spreading at 15 Hz at eye closure

L. C. B. Silva et al.

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

Patient # 4:  Generalized PPR at 60 Hz with eyes open:

13

14

Patient # 5:  Generalized PPR at 20 Hz with eyes open, but after eye blinks

L. C. B. Silva et al.

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

Patient # 6:  Occipital PPR with spreading at 30 Hz with eye closure

15

L. C. B. Silva et al.

16

Patient # 7:  generalized PPR at 13 Hz with eyes open; increase of response after eye blink

None of the epileptiform activity, either spontaneous or evoked was associated with any clinical signs, including with deltoid electromyography (EMG). None of the PPRpositive children had spontaneous discharges. Importantly, only the PPR children had a family history of epilepsy or migraine! One of the PPRpositive ones (Patient # 4) showed 3 years at the age of 11 focal seizures with a temporal focus. The prevalence of symptoms in all 175 subjects during IPS was 34.3%: 97 described pain in their eyes, 38 blurred vision, 35 illusions, 11 dizziness and 6 headache. Most described at least one symptom during IPS.  The children with a PPR

appeared no different from the total group of investigated children (see Fig. 1.3). There was no difference in reported symptoms on exposure to visual stimuli in daily life between those who were PPR-positive and those who were not. Comment: Strict exclusion criteria based on clinical history and physical examination, in combination with standardized EEG methodology and reporting, showed a prevalence of 1.4% of PPRs in normal children and adolescents. Interestingly, three of the seven PPR-positive children had a second-degree family member with epilepsy, suggesting that genetic factors do play an important role.

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

17

100 90 Number of subjects

80 70 60 50 40 30 20 10 0 pain in the eyes

blurred vision

illusions

vertigo

headache

vision of stars

Fig. 1.3  Complaints of 510 Brazilian Students during IPS, Teófilo Otoni, 2001–2002

1.2.2.1 In Summary The prevalence of PPR in healthy children and adolescents, living in Europe, the USA and Brazil ranged from 1.4 to 11.6%. Higher numbers were found in those studies with longer duration of IPS and in the age group 7–12  years. Females appeared to be more sensitive than males, possibly as high as twice as sensitive. There also appears to be an association with a positive PPR and both spontaneous epileptiform discharges and a family history of epilepsy.

1.3

Studies in People with Epilepsy

In 1948, Gastaut et al. [14] described visual sensitive epilepsy based on clinical and EEG data and found a prevalence of 4% in patients with epilepsy. Ten years later they reported the results of IPS in 4000 patients with epilepsy: spike-wave complexes were found in 15% (25% with generalized epilepsy) and parieto-occipital slow waves in 7.5% (15% with generalized epilepsy) [18]. Doose et al. [36] studied 168 children with epileptic seizures; only four of them had experienced

infrequent visually induced seizures. Febrile and afebrile generalized tonic-clonic seizures (GTCS) predominated followed by focal seizures and absences, respectively. Photosensitive epilepsies were more common in females than in males. The family histories of these patients indicated that the appearance of disease in early childhood was affected by additional genetic factors, probably independent of photosensitivity. Doose et  al. stressed that photosensitivity should be considered as a symptom of a gene-dependent functional disorder and in which virtually all recognized types of seizures and natural histories of epilepsy may be seen. Jeavons and Harding [1] investigated 460 patients with epilepsy using a Grass PS 22 (with grid) and divided them into three groups: (1) Patients with spontaneous seizures and PPRs; (2) Patients with visually induced seizures, with or without PPRs; (3) Patients with visually induced and spontaneous seizures, with or without PPRs. Visual sensitive epilepsy was more frequent between 8 and 20 years of age and the most effective frequencies of stimulation were between 15 and 20 Hz with a PPR being seen in 96% of individuals. Wolf and Goosses [37] studied 1044 patients with epileptic syndromes using a stroboscope

18

with a clear glass and a flash luminance of 750,000 lux at 50 cm from the eyes; 103 (9.9%) were photosensitive. They used increasing and decreasing frequencies from 3 to 30  Hz and patients were repeatedly asked to open and close their eyes during variable flash rates. A clinical seizure, mostly myoclonic, occurred in 46 of the 103 photosensitive patients. Photosensitivity was most commonly seen in patients whose first EEG was recorded between the ages of 10 and 25 years. The age at onset of their epilepsy (mean 14.4 years) was generally lower than that of non-­ photosensitive patients. Three fifths of the photosensitive patients were females; this gender difference was not seen in patients with epilepsy patients that were not photosensitive. Eighty-­ eight per cent of photosensitive patients experienced generalized epilepsies. Analysis by generalized epilepsy syndrome showed that only three had a clear association with photosensitivity: childhood absence epilepsy (18%), juvenile myoclonic epilepsy (30%) and epilepsy with generalized tonic-clonic seizures on awakening (13%). Kasteleijn-Nolst Trenité [3] investigated 100 patients with epilepsy that had a PPR and compared them to an age and sex-matched group without a PPR.  Patients with a PPR were more likely to experience epileptic seizures provoked by visual stimuli in daily life including looking at striped patterns and television. They were also sensitive to black and white television screens and this is discussed later in the chapter. Quick et  al. [38] were the first to study the prevalence of visual sensitive epilepsy in a general population in the UK with EEGs performed at different hospitals. They adopted the Waltz criteria of classification of PPR [39], namely: I— occipital spikes, II—parieto-occipital spikes with biphasic slow waves, III—parieto-­occipital spikes with biphasic slow waves irradiated to frontal regions, IV—synchronous, generalized, spike or polyspike-waves complexes. They found a PPR rate of 1.1 in 100,000 for all ages, 5.7 in 100,000 for ages between 5 and 19, 0.4  in 100,000 for response I and 1.27 in 100,000 for response III. Shiraisi et  al. [40] analysed the responses to IPS using a Grass PS22 and PS33  in 2187 unselected patients with epilepsy. A generalized

L. C. B. Silva et al.

PPR was elicited in 37 (1.7%) of all patients with a mean age of 17 years; 5.6% had an idiopathic generalized epilepsy, 2% had symptomatic generalized epilepsy, 0.7% had ­symptomatic localization-related epilepsy and in 2.9% the epilepsy was un-classified. Similar to the study by Wolf and Goosses, they found a high prevalence of PPR in juvenile myoclonic epilepsy (17.4%) and grand mal on awakening in 7.6%. They also found out that 6.1% had symptomatic occipital lobe epilepsy. The incidence of PPR increased in patients up to 15 years, and suddenly decreased after 20 years. Roy et al. [41] studied 1000 (723 males, 277 females) patients with epilepsy aged 8–20 years. Thirty patients (3%) were photosensitive with the maximum response seen with an IPS of 20  Hz. PPRs were more commonly seen in those with generalized tonic-clonic seizures (10 patients) and in those with mental retardation (7 patients). Bruhn et al. [42] studied 48 paediatric patients (aged 6–18  years) with a PPR, of whom 23 (48%) had a history of epileptic seizures. A Knott electronic photo-stimulator (LT1001, 1,450,000 Lux) was set at a distance of 30  cm from the nasion. With the eyes closed, the patient received a stimulus for 60 s with the frequency slowly increasing and then decreasing. The duration of the stimulus was 30 s at all used frequencies (5, 10, 12, 15, 20, 25, 30, and at 18 Hz in some individuals). After 10 s, the patients were asked to open their eyes for 3  s and then close them again. Finally, at the end of IPS, another 30-s stimulus was given at rapidly changing frequencies. If generalized spikes appeared during IPS, the procedure was stopped immediately and repeated after a short interval at the same frequency. If spikes re-appeared, IPS was interrupted again for a short time and then continued at decreasing frequencies, starting at 30 Hz. This allowed the investigators to establish the range of photosensitivity in each patient. Of the 48 that were photosensitive, 23 had previously experienced an epileptic seizure (15 with Waltz grade 3 or 4). Ten of the 17 male subjects and 13 of the 31 female subjects had experienced at least one seizure. Three patients (6.25%) had experienced focal seizures. In 17 patients, idiopathic, generalized epilepsy presented with various seizure

1  Epidemiology of Sensitivity of the Brain to Intermittent Photic Stimulation and Patterns

types (absences, generalized tonic-clonic, myoclonic, and myoclonic astatic). Un-classified seizures occurred in three subjects (6.25%). Two patients had experienced only febrile seizures. The remaining 25 patients showed repeated PPRs in a routine EEG that had been undertaken for neurological or behavioural symptoms, including headache, learning disabilities or possible epileptic seizures. Of the group of 23 subjects who had experienced epileptic seizures, 8 (35%) reported visual induced or photogenic seizures; triggers included television, video games or flickering sunlight. Six patients showed spontaneous generalized spikes and waves and 13 of the 48 patients had a family member with a PPR. Lu et  al. [43] reported a retrospective study of photosensitivity in 566 German children (244 females) with epilepsy. Thirty-one per cent had a PPR. The frequency of a PPR in generalized epilepsy (46%) was significantly higher than in focal epilepsy (20%, 23% of which had Rolandic epilepsy). The highest rate of PPR was 74% in patients with grand mal on awakening, followed by those with juvenile absence epilepsy (56%), juvenile myoclonic epilepsy (50%) and childhood absence epilepsy (44%). Studies undertaken in different countries by Danesi et al. [44], Aziz et al. [45], Saleem et al. [46] and Bai et al. [47] have shown differences in the prevalence of PPR in different genetically related populations; Caucasians seem to show the highest prevalence of PPR.

19

Comment: Caucasians appear to have a much higher prevalence of photosensitivity (10–15%) than Asians (Pakistan 0.6%, India 1.7%, China 1.3%) and Africans (1.6–3.9%). The female preponderance is however the same in all countries.

1.3.1 P  attern Sensitivity in Normal Children and Adolescents Apart from a control group of 21 healthy children and adolescents in the study by Bruhn et al. [42], the only population based study on pattern sensitivity was undertaken by Barreto Silva in 2003 [34]. This was on 510 normal individuals, aged 6–18  years randomly selected from a student population in a provincial town in Brazil (see above). Students were instructed to look six times for a duration of 10 s at the centre of a vertical black and white pattern (r = 11) at a distance of 57 cm, meaning a visual angle of 11°. Between the presentations the subject remained with their eyes closed. Epileptiform activity during pattern stimulation was not registered in this study. Similarly in the German sample, no pattern sensitivity was found [43]. Nevertheless, 87 of the 510 (17%) individuals complained of particularly blurred vision (48), and illusions (22) during pattern stimulation as compared to their complaints during IPS (see Fig. 1.4).

120 100 80 IPS P

60 40 20 0 pain in the eyes

blurred vision

illusions

Fig. 1.4  Comparison of complaints of 510 Brazilian students between IPS (seven subjects, 1.4% with a PPR) and pattern stimulation (P) (none sensitive). Blurred vision

vertigo

headache

vision of stars

feel crushed

was slightly more common with pattern stimulation; pain in the eyes was much more common with IPS (p